Inhibition of Resveratrol Analogs on Human and Rat 3β-Hydroxysteroid Dehydrogenases: Structure–Activity Relationship and Docking Analysis
Ming Su, Lei Ye, Yunbing Tang, Shaowei Wang, Zhiyan Hu, Huitao Li, Yiyan Wang, Xiaoheng Li, Yi Liu, Ren‐Shan Ge
Abstract
Resveratrol and its analogs are phytochemicals. Human 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1) synthesizes steroid hormones for normal pregnancy or promoting cancer metastasis. Whether they inhibit 3β-HSD1 remains unclear. In this study, the inhibitory potency, mode of action, structure–activity relationship, and docking parameters of resveratrol and its analogs on 3β-HSD1 and rat homolog 3β-HSD4 were analyzed. The inhibitory potency of these chemicals on human 3β-HSD1 was 4,4′-dihydroxystilbene (IC 50, 3.68 μM) > pinostilbene (8.07 μM) > pinosylvin (10.60 μM) > lunularin (26.84 μM) > resveratrol (30.20 μM) > dihydroresveratrol (>100 μM) = oxyresveratrol (>100 μM) > dihydropinosylvin (ineffective at 100 μM). Resveratrol analogs and metabolites are mixed or competitive inhibitors of human 3β-HSD1. Resveratrol and 4,4′-dihydroxystilbene inhibited progesterone secretion by human JAr cells at ≥1 μM. Resveratrol (IC 50, 32.09 μM) and pinosylvin (34.71 μM) significantly inhibited rat placental 3β-HSD4 activity. Docking analysis shows that resveratrol analogs and metabolites bind the steroid-binding sites of human 3β-HSD1 and rat 3β-HSD4 and interact with the catalytic residues Ser125/Thr125 and Tyr155. The negative correlation of Log P and IC 50 values for human 3β-HSD1 indicates that lipophilicity of chemicals plays a critical role in the inhibitory effect of chemicals. In conclusion, 4,4′-dihydroxystilbene, pinostilbene, and pinosylvin effectively inhibit human 3β-HSD1 depending on their lipophilicity, thereby acting as potential therapeutic agents.